PL186702B1 - Method of increasing optical purity of enantiomerically anriiched derivatives of benzimidazole - Google Patents

Abstract

1. Method for increasing the enantiomeric excess in enantiomeric mixtures enriched in one of the individual enantiomers of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, characterized in that said mixture is treated at room temperature or below with an organic solvent selected from the group consisting of ketone, ester, alcohol, nitrile, hydrocarbon and ether, the precipitated racemate is filtered off, and the solvent is then removed from the filtrate by distillation or evaporation , preferably by evaporation. PL PL PL PL PL PL PL PL

Description

The present invention relates to a method of increasing the enantiomeric excess in enantiomeric mixtures enriched in one of the single enantiomers of 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole.

5-Methoxy-2 - [[(4-methoxy-3,5-dimethylTo-2-pyritylnyl) methyl] sulfinyl-1H-benzimidazole of the formula below,

Omeprazole H and therapeutically acceptable salts are described in EP 5129. Omeprazole and its alkali metal and alkaline earth metal salts are effective inhibitors of gastric acid secretion and are useful as antiulcer agents.

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Omeprazole has a chiral center at the sulfur atom and can therefore exist in the form of two stereoisomers (enantiomers).

Despite the description in the scientific literature in the late seventies of the group of chiral sulfoxides of the 2- (pyridinylmethylsulfinyl) -1H-benzimidazole type, including omeprazole, an efficient method of asymmetric synthesis of its single enantiomers has not yet been described.

Single enantiomers are of increasing interest due to their better pharmacokinetics and better biological properties. Therefore, there is a need for a method that can be used on a large scale to produce single enantiomers of omeprazole.

In general, processes for the asymmetric synthesis of chiral sulfoxides yield optically active sulfoxides in enantiomerically enriched forms rather than in pure single enantiomeric forms, unless the processes are enzymatic transformations or are based on resolution methods. Therefore, there is also a need for a method that can be applied on a large scale, allowing the enantiomeric excess of enantiomeric mixtures enriched in one of the single enantiomers of the optically active omeprazole to be increased.

DE 4035455 and WO 94/27988 describe processes for the separation of various substituted 2- (2-pyridinylmethylsulfinyl) -1H-benzimidazoles, including reaction steps in which a diastereomeric mixture is synthesized from the racemate of an appropriately substituted 2- (2-pyridinylmethylsulfinyl) -1H -benzimidazoles. The diastereoisomers are then separated and finally the separated diastereoisomer is converted into optically pure sulfoxide in a hydrolysis step. These methods of separating diastereoisomeric intermediates suffer from at least three major disadvantages, namely:

1) The substituted 2- (2-pyridinylmethylsulfinyl) -1H-benzimidazole as a racemic intermediate has to be further converted in several reaction steps before obtaining single enantiomers.

2) The separation processes involve complex separation steps.

3) There is a large loss of highly pure substance when the unwanted stereoisomer of the opposite diastereoisomer is discarded.

In Euro. J. Biochem., 166 (1987), pp. 453-459 disclose enantiomeroselective methods for the synthesis of a 2- (2-pyridinylmethylsulfinyl) -1H-benzimidazole derivative, namely single enantiomers of the sulfoxide agent (5,7-dihydro-2 - [(4 -methoxy-3-methyl-2-pyridinyl) methyl] sulfinyl] -5,5,7,7-tetrinaunethylidene- [5,6-d] -imidazole-6- (1H) -one). This process is based on the enantiomeroselective oxidation of the corresponding pro-chiral sulfide to this sulfoxide. It was found that crude sulfoxide, having an enantiomeric excess (n.e.) of about 30%, could be purified to optically pure sulfoxide [(n.e.)> 95%] using a series of crystallization steps. However, the yield and the number of crystallization steps are not disclosed.

However, this proposed crystallization process is not suitable for a type of compound such as omeprazole.

Surprisingly, it turned out that omeprazole racemates can be very selectively precipitated from the solvent, giving single enantiomers with increased optical purity.

The invention therefore relates to a method of increasing the enantiomeric excess in enantiomeric mixtures enriched with one of the single enantiomers of 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole, which characterized in that this mixture is treated at room temperature or below with an organic solvent selected from the group consisting of ketone, ester, alcohol, nitrile, hydrocarbon and ether, the precipitated racemate is filtered off, and then the solvent is removed from the filtrate by distillation or evaporation, preferably by evaporation.

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Preferably, an enantiomeric mixture enriched in a single (-) - enantiomer or a single (+) - enantiomer 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyrid-2-yl) methyl] is used in the process according to the invention. sulfmyl] -1H-benzimidazole.

In the process according to the invention, an organic solvent mixture is preferably used as the organic solvent.

Preferably, one or more organic solvents are used in admixture with water in the process of the invention.

In the process according to the invention, acetone, acetonitrile or toluene is preferably used as the organic solvent.

The precipitation is carried out in a protic or aprotic solvent. The solvent facilitates crystallization and is necessary for separation. The choice of the solvent from which the racemate is precipitated is not critical to the process. The preferred solvent is an organic solvent. A suitable organic solvent is a ketone such as acetone or 2-butanone, an ester such as ethyl acetate, an alcohol such as ethanol, a nitrile such as acetonitrile, or a hydrocarbon such as toluene. The solvent may also be an ether. In addition, any other organic solvent from which the omeprazole racemate can be selectively precipitated may be used. The solvent may also be a mixture of various organic solvents. The preferred solvent is acetone, acetonitrile or toluene.

The temperature is not an important parameter in the process of the invention. However, if the temperature is too high, the solubility increases, the selectivity decreases, and the compound decomposes. Therefore, room temperature is preferred, but temperatures below room temperature are also suitable.

Another advantage of the process according to the invention is that, surprisingly, the omeprazole racemates crystallize very selectively from the organic solvent. In the mother liquor (filtrate), an extremely increased enantiomeric excess of the (-) - enantiomer or (+) - enantiomer of omeprazole is obtained, even after one crystallization of the racemate. Therefore, the process is highly efficient. As a result, single enantiomers can be obtained with very high enantiomeric excess, even from optically impure mixtures. This means that high enantiomeroselectivity is not critical to the asymmetric synthesis of such optically active compounds, ie the asymmetric oxidation of the corresponding pro-chiral sulfides. Thus, in selecting the most appropriate methods of asymmetric synthesis of omeprazole, a wider range of synthetic methods can be considered. For example, chemical yield, reagent cost, reaction time, and the degree of hazardous handling of the reagents can be as important considerations as the enantiomeroselectivity when selecting a synthesis method.

Examples 1-9 illustrate the method of the invention.

The enantiomeric excess value in each of the following examples is indicative of the relative amount of each enantiomer. Value is defined as the difference between the relative percentages of the two enantiomers. For example, when the percentage of the (-) - enantiomer of omeprazole is 97.5% and the percentage of the (+) - enantiomer is 2.5%, the enantiomeric excess of the (-) - enantiomer is 95%.

The enantiomeric composition of omeprazole was determined by chiral HPLC, either on a Chiralpak AD column or on a Chiral AGP column, under the following conditions:

Chraalpak AD column 50 x 4.6 µm

Eluent (100 ml), ethanol (100 ml) and acetic acid (10 μΐ)

0.5 ml ^ mm 50 μΐ

302 rmi 4.0 min 5.8 min

Example 1. Increasing optical purity from 60% C.E. up to 98.4% CE (-) - 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole

Flow

Injection volume Wavelength

Retention time for the (-) - enantiomer Retention time for the (+ 1-enantiomer

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2.35 g of a mixture of 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyrid; yiyl) methyl] sulfinyl] -1H-benzimidazole enantiomers were dissolved in 20 ml of acetonitrile in the form of a yellow syrup (60 % ne in favor of the (-) - enantiomer). Almost immediately thereafter a racemate precipitate appeared and after 30 minutes in the refrigerator, this white precipitate was filtered off. The solvent was evaporated from the filtrate to give 1.2 g of the (-) - enantiomer of omeprazole in the form of a yellow syrup with optical purity of 98.4% C.E.

Example 2. Increasing the optical purity from 20% nedo 91.4% ne (-) - 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H- benzimidazole

2.35 g of a mixture of 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole enantiomers were dissolved in 20 ml of 2-butanone in the form of a yellow syrup ( 20% ne in favor of the (-) - enantiomer). Almost immediately thereafter a precipitate of the racemate appeared and after one hour in a refrigerator, this white precipitate was filtered off. The solvent was evaporated from the filtrate to give 0.48 g of the (-) - enantiomer of omeprazole in the form of a yellow syrup with optical purity 91.4% C.E.

Example 3. Increasing the optical purity from 50% C.E. up to 97.3% CE (-) - 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyrid} ylyl) methyl] sulffnyl] -1H-benzimidazole

2.35 g of the enantiomer mixture of 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-ρiiyd; ylyl) methyl] sulfinyl] -1H-benzimidazole were dissolved in 20 ml of acetone in the form of a yellow syrup (50 % ne in favor of the (-) - enantiomer). Almost immediately thereafter a precipitate of the racemate appeared and after one hour in the refrigerator this white precipitate was filtered off. The solvent was evaporated from the filtrate to give 1.0 g of the (-) - enantiomer of omeprazole in the form of a yellow syrup with an optical purity of 97.3% C.E.

Example 4. Increasing the optical purity from 80% C.E. up to 95.4% CE (+) - 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole

2.35 g of the enantiomer mixture of 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole are dissolved in 20 ml of ethyl acetate as a yellow syrup (80% in favor of the (+) - enantiomer). Almost immediately thereafter a precipitate of the racemate appeared and after one hour in a refrigerator, this white precipitate was filtered off. The solvent was evaporated from the filtrate to give 1.7 g of the (+) - enantiomer of omeprazole in the form of a yellow syrup with an optical purity of 95.4% C.E.

Example 5. Increasing the optical purity from 40% C.E. up to 88.7% CE (+) - 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole

2.35 g of the enantiomer mixture of 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyrid} ^^ yl) methyl] sulphnyl] -1H-benzimidase; ol was dissolved in 20 ml of ethanol. yellow syrup (40 ne in favor of the (+) - enantiomer). Almost immediately thereafter a precipitate of the racemate appeared and after one hour in a refrigerator, this white precipitate was filtered off. The solvent was evaporated from the filtrate to give 1.0 g of the (+) - enantiomer of omeprazole in the form of a yellow syrup, optical purity 88.7% C.E.

Example 6. Increasing the optical purity from 30% C.E. up to 97.0% CE (+) - 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole

2.35 g of the enantiomer mixture of 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-plridium-4-yl) methyl] sulfmyl] -1H-benzimidazole are dissolved in 20 ml of toluene in the form of a yellow syrup ( 30% ne in favor of the (+) - enantiomer). Almost immediately thereafter a precipitate of the racemate appeared and after one hour in a refrigerator, this white precipitate was filtered off. The solvent was evaporated from the filtrate to give 0.62 g of the (+) - enantiomer of omeprazole in the form of a yellow syrup with optical purity equal to 97.0% C.E.

Example 7. Asymmetric synthesis of (+) - 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfonyl] -1H-benzimldazole followed by optical purity increase

A mixture of 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio-1H-benzimidazole (0.47 g, 1.46 mmol), (3'S, 2R) - ( -) - N- (phenylsulfonyl) -3,3-dichlorocamphoryl) oxaziridine (0.55 g, 1.46 mmol), triethylamine (0.07 ml, 0.5 mmol) and 20 ml of carbon tetrachloride were stirred at ambient temperature for 96 hours. After removal of the solvent, the residue was dissolved in methylene chloride (25 mL). Extract the mixture

Was mixed with two portions of aqueous sodium hydroxide solution (0.1 M, 15 ml). The combined aqueous solutions were neutralized with an aqueous ammonium chloride solution in the presence of methylene chloride. The formed phases were separated and the aqueous solution was extracted with two portions of methylene chloride. The combined organic solutions were dried over sodium sulfate and then the solvent was removed. The residue (200 mg, 40% ee) was dissolved in 2-butanone (3 ml) and the formed precipitate was filtered off. The solvent was evaporated from the filtrate to give 0.11 g (22%) of the title compound with an optical purity of 94% n.e.

Example 8. Asymmetric synthesis of (-) - 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole followed by optical purity increase

1.6 kg (5.0 mol) of 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -1H-benzimidazole were dissolved in 5.0 L of ethyl acetate. 31 ml (1.7 mol) of water was added to the solution. To the mixture was added 856 ml (5.0 mol) of ethyl (-) - D-tartrate, 744 ml (2.5 mol) of titanium (IV) isopropoxide and 435 ml (2.5 mol) of diisopropylethylamine at room temperature. Then 830 ml (4.5 mol) of cumene hydroperoxide were added at 30 ° C. After stirring for one hour at 30 ° C, the reaction was complete. Analyzes by chiral and achiral chromatography showed the mixture to be 71.4% sulfoxide with an enantiomeric excess (n.e.) of 72.9%. The mixture was cooled to 10 ° C and after addition of 1.7 L of isoacetate the product was extracted three times with aqueous ammonia solution (12%), total volume 101. The combined aqueous phases were neutralized by adding 1.5 L of concentrated acetic acid in the presence of acetate. ethyl (3 L). The solvent was removed from the combined organic layers and acetonitrile (1.5 L) was added at the end of the evaporation to aid removal of the solvent. Acetone (2.5 L) was added to precipitate the omeprazole racemate, which was then filtered off (254 g). Analysis of the filtrate by HPLC (achiral and chiral columns) showed that this solution was 88% sulfoxide with an optical purity of 96.3% C.E. and thus the optical purity was increased from 72.9% CE up to 96.3% CE, simply in one operation to precipitate racemic omeprazole. Moreover, analysis (HPLC) of the filtrate content showed that the yield was 0.8 kg (46%). The (-) - enantiomer of the 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzirmdazole was not isolated in its neutral form but was further converted to the corresponding sodium salt.

Example 9. Asymmetric synthesis of (+) - 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole followed by increasing optical purity

1.6 kg (5.0 mol) of 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -1H-benzimidazole were dissolved in 7.5 L of ethyl acetate. 31 ml (1.7 mol) of water was added to the solution. To the mixture was added 856 ml (5.0 mol) of (+) - ethyl L-tartrate, 744 ml (2.5 mol) of titanium (IV) isopropoxide and 436 ml (2.5 mol) of diisopropylethylamine at room temperature. Then 830 ml (4.5 mol) of cumene hydroperoxide were added at 30 ° C. After stirring for one hour at 30 ° C, the reaction was complete. Analyzes by chiral and achiral chromatography showed the mixture to be 75% sulfoxide with an enantiomeric excess (n.e.) of 80%. The mixture was cooled to 10 ° C and after the addition of 1.5 L of isoacetate and ethyl acetate (0.5 L) the product was extracted three times with an aqueous ammonia solution (12%), total volume 14 L. The combined aqueous phases were neutralized by adding 1 5 L of concentrated acetic acid in the presence of ethyl acetate (4 L). The phases were separated and the aqueous phase was extracted with ethyl acetate (4 L). Solvent was removed from the combined organic layers. Acetone (3.0 L) was added to precipitate the omeprazole racemate, which was then filtered off (254 g). Analysis of the filtrate by HPLC (achiral and chiral columns) showed that the solution was 90% sulfoxide with an optical purity of 95% n.e. and thus the optical purity was increased from 80% CE up to 95% CE, simply in one operation to precipitate racemic omeprazole. In addition, analysis (HPLC) of the filtrate content showed that the yield was 1.0 kg (58%). The (+) - enantiomer of the 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole was not isolated in its neutral form but was further converted to the corresponding sodium salt.

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Claims (6)

Patent claims 1. A method for increasing the enantiomeric excess in enantiomeric mixtures enriched in one of the single enantiomers of 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole, characterized by the mixture is treated at room temperature or below with an organic solvent selected from the group consisting of ketone, ester, alcohol, nitrile, hydrocarbon and ether, the precipitated racemate is filtered off, and then the solvent is removed from the filtrate by distillation or evaporation, preferably by evaporation. 2. The method according to p. A process as claimed in claim 1, characterized in that the enantiomeric mixture enriched in the single (-) - enantiomer 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole . 3. The method according to p. The process of claim 1, wherein the enantiomeric mixture is enriched in the single (+) - enantiomer 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole. 4. The method according to p. 3. The method of claim 1, 2 or 3, characterized in that a mixture of organic solvents is used as the organic solvent. 5. The method according to p. 1, 2 or 3, characterized in that one or more organic solvents are used in a mixture with water 6. The method according to p. The process of claim 1, 2 or 3, characterized in that acetone, acetonitrile or toluene is used as the organic solvent.